Diacyldipyrromethanes are critical intermediates in porphyrin synthesis. P. Rao et al., J. Org. Chem. 2000, 65, 7323-7344. The reduction of a 1,9-diacyldipyrromethane affords the corresponding diol, which upon reaction with a dipyrromethane affords the meso-substituted porphyrin. With a diacyldipyrromethane bearing A, B, and C substituents at the 1, 5, and 9 positions, respectively, and a dipyrromethane bearing a D substituent at the respective 5-position, porphyrins bearing up to four different meso-substituents are readily prepared (ABCD-porphyrins). The availability of diacylation procedures that are efficient, mild, and scalable is essential for the smooth preparation of diverse porphyrins.
The methods for acylation of a dipyrromethane depend on whether the substituents at the 1- and 9-positions are the same or different. With identical substituents, the dipyrromethane (1) can be treated with excess EtMgBr, generating the dipyrromethane analog of the “pyrrole Grignard reagent,” followed by excess acid chloride. The reaction typically yields a mixture of the intermediate 1-monoacyldipyrromethane (2) and the desired 1,9-diacyldipyrromethane (3) (Scheme 1). Diacyldipyrromethanes rarely crystallize well. Accordingly, the mixture is usually separated by chromatography, which can be tedious owing to the tending of the acyl-dipyrromethanes to streak on chromatographic media. Other methods of diacylation different from those of Scheme 1 are also available.
With different substituents at the 1- and 9-positions, a stepwise synthesis is required. The first step entails reaction of the dipyrromethane with EtMgBr followed by a 2-S-pyridyl benzothioate, which exclusively and efficiently gives the monoacyldipyrromethane (2). P. Rao et al., J. Org. Chem. 2000, 65, 1084-1092. Reaction of the latter with EtMgBr followed by an acid chloride is employed to obtain the 1,9-diacyldipyrromethane (3). P. Rao et al., J. Org. Chem. 2000, 65, 7323-7344. Again, the diacyldipyrromethane is purified by chromatography. If acylated sequentially, the 1- and 9-substitutents (R2) can be different.
There remains a need for improvements in the synthesis of diacyldipyrromethanes, particularly for the introduction of two identical substituents. Indeed, the limitations of the one-step diacylation procedure are such that the two-step procedure is often employed instead. The acylation of a dipyrromethane at both α-positions would seem to be a straightforward matter, given the various methods available for the facile acylation of pyrrole. H. Anderson, et al., In Pyrroles. Part I, Jones, R. A.; Ed., John Wiley & Sons, Inc.: New York, 1990, pp 397-497. However, the diacylation of the dipyrromethane must be done under conditions that do not cause acidolysis of the linkage joining the two dipyrromethanes.